Confounding association between plasma HDL‐C levels and increased fracture risk: A correspondence

Abstract Background This article explores the association between fractures, particularly in the elderly, and elevated plasma high‐density lipoprotein cholesterol (HDL‐C) levels. The study challenges the conventional idea of HDL‐C as “good cholesterol” by revealing its potential role as a risk factor for fractures. Factors contributing to fractures in the elderly, such as diminishing bone strength due to aging‐related tissue breakdown, are discussed. Sedentary lifestyles, low bone mineral density (BMD), and habits like smoking and alcohol consumption compound fracture susceptibility. Materials and Methods The study delves into mechanisms linking elevated HDL‐C to fractures, using data from the ASPREE‐Fracturesub‐study of the ASPREE trial involving Australian and American participants aged 65 and above. Results The study showed that over a 4‐year period, elevated HDL‐C levels in healthy older people were linked to a 14% higher fracture risk. This revelation expands the understanding of fracture risk factors beyond the established norms. Conclusion The article emphasizes the need to reconsider HDL‐C's traditional role as an indicator of cardiovascular health, particularly in light of medications like Statins and Anacetrapib that raise HDL‐C levels. It calls for further exploration into the relationship between HDL‐C, fractures at varying sites, and different age groups. Practical implications involve incorporating fracture risk associated with high HDL‐C into clinical considerations, alongside advocating lifestyle changes for optimal HDL‐C levels. In summary, this study prompts a reevaluation of HDL‐C's implications in clinical practice, demanding further investigation into the intricacies of this relationship.


| INTRODUCTION
The ageing process involves significant risk factors such as the gradual breakdown of tissue structure and the impairment of physiological function across a number of systems, which can manifest most noticeably in a decrease in lower limb strength.Since bones have a natural tendency to become fragile over the years, the majority of fractures occurring in individuals over the age of 60 are induced by a combination of weak bones and falling. 1 Lack of physical activity is also a leading cause of fractures in elderly as older individuals with low bone mineral density (BMD) tend to fracture more frequently, and regular exercise has been proven to raise BMD. 2 Additionally, smoking, a low body mass index, insufficient calcium intake, and alcohol overconsumption increase the likelihood of fractures in the elderly. 3

| High HDL-C levels and fracture risk
Recently, a cohort study makes the novel finding that plasma highdensity lipoprotein cholesterol (HDL-C) levels in healthy older persons are linked to an increased risk of fracture.As a distinctive aspect of the study, the term "healthy" refers to the absence of cardiovascular disease, dementia, physical disability, or lifethreatening chronic illnesses among the participants.Based on a post-hoc analysis of data from the ASPREE-Fracture sub-study of the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial, the investigation found that a one standard deviation rise in HDL-C levels was related to a 14% increased likelihood of fracture over a 4year period (HR, 1.14; 95% CI, 1.08-1.20),hence augmenting conventional risk factors for fracture. 4Since the Framingham study of the healthy population, HDL-C has been termed "good cholesterol" yet recent findings have been contrary to this popular belief. 5That being so, the purpose of this article is to explore the association between raised plasma HDL-C levels and increased fracture risk.We also delve deeper to identify further negative consequences on human health caused by elevated HDL-C levels.
Therefore, the message of this article is; should this association prove to be accurate, it must be applied to management strategies going forward.Although higher levels of HDL-C have been linked with osteoporosis in a recent meta-analysis, 6 and preclinical studies have revealed that HDL-C lowers bone mineral density (BMD) by decreasing the quantity and function of osteoblasts, 7 the pathways through which an increased HDL-C level may lead to fracture remain ambiguous.A significant possibility could be factors such as physical exercise, which may result in greater HDL-C levels but also raise the chances of fracture.However, the validity of this explanation is weakened by the fact that fracture risk remained relatively constant when participants who practised light to vigorous workouts were omitted from the study.Additionally, pathophysiological reasoning may be indicated by a Mendelian randomisation study demonstrating a genome-wide connection between raised HDL-C and poor BMD. 8 HDL-C levels were also identified as a causative risk factor for reduced heel and lumbar spine BMD in a review of genome-wide association studies. 9

| Methods employed in original study and various articles supporting this association
As part of the ASPREE study between 2010 and 2014, 16,703   Australian and 2411 American healthy older adults aged ≥70 years and ≥65 years were enlisted, respectively.The trial conducted annual checkups, during which fasting lipid levels (including HDL-C and non HDL-C) were measured along with anthropometric and laboratory data.Following randomisation, Australian participants in the ASPREE fracture sub-study provided information on incident fractures.Thus, a team of specialized doctors and researchers categorized all reported fractures according to etiology and site (e.g., vertebral, hip, non-hip).Medical imaging was utilized to diagnose the traumatic and minimal trauma fractures.Lastly, hazard ratios were computed using cox regression and an HR curve was used to analyse the potential link between HDL-C levels and fractures. 4Furthermore, the evidence of a connection between HDL-C levels and fractures is rising as a result of multiple investigations conducted globally.A cross-sectional study carried out in the Xuhui and Yangpu districts of the Shanghai metropolitan area, China consisting of 1791 participants older than 55 years, reported a strong correlation between per standard deviation increase in HDL-C levels and a higher risk of osteoporotic fractures in total participants and women. 10Likewise, according to a meta-analysis, individuals with a lower HDL level (<40 mg/dl) had a lesser chance of bone fracture than those with a normal level (≥40 mg/dl). 11A 5832-person observation from the Cardiovascular Health Study found a further positive correlation: a high cholesterol and lipoprotein profile increases the risk of hip fracture. 12Similar to this, a thorough investigation of the pathophysiology of elevated HDL-C and the risk of osteoporotic fractures was conducted by comparing bone mineral density to HDL-C, which revealed that 214 postmenopausal women had lower BMD in selected regions with high HDL-C values. 13Thus, these studies highlight how elevated HDL-C levels are associated with weaker bones and increase the risk of fracture.

| Potential adverse effects of high HDL-C levels
The implication of increased HDL-C quantities being a traditional risk factor for fractures shifts attention towards additional adverse effects of extremely high plasma levels of this cholesterol.Recent studies have shown that HDL-C is a poor indicator of the positive functions of high density lipoproteins and cannot be used to reflect the structural and functional properties of the lipids and proteins present in HDL.These factors demonstrate that HDL-C is a poor target for medication therapy, especially in light of the consistent failure of drug trials. 14HDL-C dysfunction amplifying illness was also seen in populations with pre-existing conditions such as coronary heart or kidney disease.High levels of HDL-C caused impairment in positive vascular effects, such as enhancing LDL-induced monocyte chemotactic activity by cells in artery wall and increasing LDL oxidation, thus contributing to the anti-atherogenic properties of HDL-C. 15Additionally, latest studies of genetic mutations in APOA1 (apolipoprotein A-I), a major gene of high density lipoprotein, show a direct association with increased risk of ischemic heart disease which is independent of plasma levels of HDL-C. 16Encouraging current chronic disease in older adults, HDL-C has been shown to enhance any present systematic inflammation that occurs with age. 17These aforementioned observations, further highlighted in Table 1, help us recognize that raising HDL-C through drug therapy has negative consequences in healthy older adults due to its inherent damaging properties.

| CONCLUSION
The results of the cohort study under discussion 4  and further study is required to identify the quality of HDL and the molecular basis underlying this association.Nevertheless, clinicians must take into account the detrimental effects of high HDL-C levels when considering the potential advantages of these medications, particularly for the elderly.Given that an average level of 89 mg/dl of HDL-C (the highest quintile in the cohort study) has been associated with a 33% higher risk of fracture, 4 it is evident that measuring HDL-C is applicable to people at risk of fracture.However, additional investigation is required to guarantee its reliability and necessity.Moreover, fracture prevention in the elderly population has conventionally included Vitamin D3 and calcium supplementation. 19To avoid fractures, maintaining normal HDL-C levels must also be crucial in clinical practice.
Ideally, the recommended strategy for raising HDL-C levels within a healthy range is through lifestyle modification. 20corporating a diet rich in unsaturated fatty acids, smoking cessation, aerobic exercise, and weight loss are essential lifestyle changes that have been reported to raise HDL-C. 21To include the consequences of high plasma HDL-C levels in future management plans, further research is required to ascertain whether there is an increased tendency for fractures to develop at specific sites (e.g., hip or vertebrae) and if this association holds true for people of all age groups.
The clinical findings about fractures, their prevention, and their relationship to HDL-C are mentioned in this table.It also delves into the various adverse impacts of HDL-C that have been discovered over time.The results were reached following a thorough literature review, with citations listed in the aforementioned table.
are relevant in clinical practice, particularly in light of the adverse effects of atheroprotective medications that significantly raise plasma HDL-C quantities.Notable drugs such as Statins17 and Anacetrapib18 reduce the risk of cardiovascular disease, primarily by lowering LDL aided by the ability to also increase HDL-C.The pathways through which HDL-C (in physical activity or drugs such as statins) is related to a greater risk of fracture remain unclear,4 Relevant literature summary.
T A B L E 1 (Continued)